09-04-08 Blackwell- FDA Draft Guidance on Process … utilized for feedback and feed forward in real...

The New Draft FDA Guidance on Process Validation- What Does it Mean

for You?

James Blackwell, Ph.D. M.B.APEGS

April 6-10, 2009Protein Scale-up and Manufacturing

Boston, MA

From Clone to Commercial®

Overview• Introduction

• Definitions

• Regulatory Background and History

• Overview of New Guidance

• What Does it Mean for You?

• Concluding Thoughts

• Appendix‐ Other Definitions


Introduction


Change can Present Opportunity

• The current pace of regulatory change in our industry is unprecedented

• Companies and individuals need to monitor these changes and ascertain the impact to their companies and areas of responsibility

• Successfully doing so can mean the difference between success and failure for a company, new product, and for you

• Nevertheless, this change represents opportunity that can add value to organizations if managed properly and can increase likelihoods of success


Desired QbD State

continual improvement enabled within design space

reactive to problems & OOS; post-approval changes needed

Lifecycle management

risk-based; controls shifted upstream; real-time release

mainly by intermediate and end product testing

Control strategy

part of overall quality control strategy; based on product performance and safety in clinic

primary means of quality control; based on batch data

Product specification

PAT utilized for feedback and feed forward in real time

in-process testing for go/no-go; offline analysis

Process control

adjustable within design space; continuous verification within design space; focus on control strategy

locked down; validation on 3 batches; focus on reproducibility

Manufacturing process

more science based; systematic; multivariate experiments, focus on unit operation outputs

empirical; typically univariateexperiments

Development/Design

Desired QbD StateCurrent StateAspect


Definitions of Process Validation- (Existing)• “Establishing documented evidence which provides a high degree

of assurance that a specific process will consistently produce aproduct meeting its pre‐determined specifications and qualityattributes” ‐ FDA Guideline, 1987

• “The action of proving, in accordance with the principles of GMP,that any procedure, process, equipment, material, activity or system actually leads to the expected results” ‐ EUDRA, 1998

• “The means of ensuring and providing documentary evidence that processes (within their specified design parameters) are capable of consistently producing a finished product of the required quality” ‐ EMEA, 2001


Definition of Process Validation – (New Guidance)

• “The collection and evaluation of data, from the design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.”


How Process Validation Is Currently Being Done• Process Development

• Define Critical Quality Attributes* (CQA), Critical Process Parameters* (CPP) and interrelationships

• Determine “Worst Case” values of CPP

• Validation Master Plan Validation Protocols• Perform performance qualification runs with qualified equipment

• Under normal and “challenge” conditions

• Define acceptable CPP ranges

• Manufacture conformance (validation) lots under cGMP• Full scale, usually three consecutive lots

• Review manufacturing data from routine production• QA System to determine if changes are needed

• And if they require re‐validation

*See Appendix for definition


How This Will Be Done - The Three Stages• Product Lifecycle View

• Stage 1: Process Design

Defining the commercial process

Based on development & scale‐up experience

Creating a Design Space* for each significant process unit operation – ideal situation

• Stage 2: Process Qualification

Confirming that the process design is capable of reproducible commercial manufacturing

• Stage 3: Continued Process Verification

Gaining ongoing assurance during routine production that the process remains in control

• Any stage can feed‐back into a previous stage at any time*See Appendix for definition


In Both Cases…• Validation depends upon knowledge and understanding of:

• The sources of variation in a process

• How these may be detected

• What is the degree of variation that may occur

• What is the impact on the process

• And on the product

• How to control the variation commensurate with the risk that it poses

• All of which should be handled by a risk evaluation program, using information from process development experiments(ICH Q9: Quality Risk Management*)



What’s in it for you?

• Hopefully, post‐approval changes and filings globally will become easier and more standardized

• With proper implementation and use

• Faster time to clinic and commercial

• Increased probability of first time approval

• Reduced regulatory burden for commercial process

• Improved process robustness (product quality) and lower COGs


Regulatory Background and History


Guidances and Timeline • 1987‐ Guideline on General Principles of Process Validation, Food and Drug

Administration

• Around the beginning of this decade, FDA became more concerned about the state of manufacturing and costs to companies and to the Agency itself

• 2004‐ Pharmaceutical cGMP for the 21st Century Initiative• PAT Guidance for Industry—A Framework for Innovative Pharmaceutical

Development, Manufacturing and Quality Assurance

• 2004‐ QbD concepts introduced into FDA review process

• 2006‐ (ICH) guidelines: • Q8 Pharmaceutical Development

• Q9 Quality Risk Management

• Q10 Quality Systems Approach to Pharmaceutical cGMP Regulations

• April, 2008‐ Concept paper for Q11: Development and Manufacture of Drug Substances (chemical entities and biotechnological/biological entities). Finalization expected in 2010

• November, 2008‐ Draft validation guidance. Final expected late 2009


Background to the New Guidance• Completed under auspices of GMPs for the 21st Century initiative

• To foster innovation and advance the science of the pharmaceutical manufacturing

• Aligns process validation activities with the product lifecycle

• Approach aligns with Quality by Design (QbD) initiative

• Builds on the concepts delineated in the 1987 Guideline

Grace E. McNallyFDA CDER Office of Compliance

Division of Manufacturing & Product Quality


…Must Comply with the Regulations …• 21 CFR 211.110: In‐process Controls ‐

• …control procedures shall be established

• to monitor the output of and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in‐process material and the drug product

• Valid in‐process specifications for such characteristics

• shall be consistent with drug product final specifications …

• shall be derived from … process average and process variability estimates …

• and determined by the application of suitable statistical procedures where appropriate


Response to Comments Regarding 211.110

• Further, after product histories are developed, the Commissionerencourages manufacturers to perform statistical analyses on their products and processes with a view to controlling batch‐to‐batch variability to the maximum extent possible.

1978 Preamble


More on 211.165….

• Section 211.165 is therefore modified to allow greater latitude in establishing acceptance criteria, while retaining the basic requirements that acceptance criteria for sampling and testing, and for acceptance levels, be based on appropriate statistical quality control criteria

• The Commissioner is convinced that sound statistical methodology should be applied to the procedures for testing of attributes or variables that impact on the quality of drug productsand the evaluation of the results of such testing to determine acceptance or rejection of the lot

• The Commissioner believes that more study must be given to this aspect of manufacturing practice…


Statistical Quality Control Criteria

• 21 CFR 211.165(d) Acceptance criteria for the sampling and testing conducted by the quality control unit shall be adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release. The statistical quality control criteria shall include appropriate acceptance levels and/or appropriate rejection levels.


Overview of New Guidance


The Life-Cycle Approach

• Necessitates comprehensive process design to understand sources of variability and achieve process understanding

• Overall validation is not “completed”, but ongoing

• Incorporates risk management

• Recognizes that more knowledge will be gained during commercialization

Grace McNally, FDA


Stage 1: Process Design• Process design studies

• Should follow ICH Q8(R1) Pharmaceutical Development and Q10 Pharmaceutical Quality System*

• Sound scientific principles, using DoE

• Multivariate studies of interrelationships between critical process parameters* (CPPs)

• Use scaled‐down experiments and modeling

• cGMP for processes impacting on drug safety

e.g., viral clearance studies

• Good documentation practices needed

• “Testing to failure” is NOT required



Stage 1: Process Design• Consider effect of commercial‐scale equipment

• Operational variability

• Instrumentation

• Limitations of control mechanisms

• Consider other sources of variation• Different lots of materials, reagents

• Operating staff capabilities

• Environmental conditions

• Measurement systems (instrumentation)

• Control of all significant unit operations, including high‐risk manufacturing operations, e.g.• Viral clearance

• Aseptic processing (sterilization, filling)


Stage 1: Process Design Studies for Biologics• Design phase studies should include the following areas:

• Material inputs, including handling

• Cell line characterization

• Upstream process steps, including bioreactor and capture steps

• Downstream purification steps

• Drug substance stability, including intermediate steps, process solutions, and freeze ‐ thaw studies

• Drug substance storage, filling, and shipping

• Mixing studies of process solutions

• Lifetime of chromatography resins and reusable filter membranes

• Viral inactivation and reduction

• Impurity clearance


Stage 1: Process Design Strategy for Process Control• To reduce input variation

• To reduce variation during manufacture

• To reduce impact on output, particularly for critical variables,unit operations, and process

• Controls can include:

• Materials analysis: starting, in‐process, final

• Equipment monitoring and control

To remain within operational limits

• Using PAT, if possible (FDA 2004 Guidance)

• Appropriate control strategy should be based on a risk assessment


Stage 1: Process Design Risk Analysis• Process risk assessment evaluations should be based on science,

prior experience, process and scale‐down data and characterization

• Performed on the source and quality of all materials and on all manufacturing processes. • The impact on critical product quality attributes, such as

identity, strength, potency, purity, safety and efficacy should be evaluated.

• In conjunction with experiments, helps identify CQAs and critical unit operations and, thus, can be very useful in prioritizing process development and characterization activities

• Used to identify a comprehensive and appropriate control strategy‐ both process controls and for evaluating changes as part of change control


Stage 2: Process Qualification

• Starts with the documentation and approval of the

Stage 1 Outputs, including:

• Clearly defined processes and controls

• Operational limits and ranges

• Specifications for in‐process intermediates and final product

• Involves technology transfer from development to production

• Uses commercial production and control documentation (the master batch record)

• Objective is to generate scientific evidence that the process iscapable of making product that can consistently meets quality acceptance criteria


Stage 2: Two Phases of Process Qualification

1. Design of facility and qualification of equipment and systems

• Includes HVAC, WFI, Clean Steam

2. Qualification of actual process performance

• Under commercial conditions


Stage 2: Facility/Equipment Qualification• Has Three Stages, according to a Qualification Plan:

• Design Qualification (DQ), based on user requirements

Selecting equipment, utilities, systems suitable for the task

• Installation Qualification (IQ)

Verifying equipment is built and installed according to the design specifications

Properly connected and calibrated

• Operational Qualification (OQ)

Equipment, system, operates according to process requirements, in all anticipated operating ranges

• All must be fully documented


Stage 2: Process Performance Qualification

• Uses the qualified facility and equipment, approved materials, trained personnel, to run the manufacturing processes according to the master batch record to produce commercial batches

• The objective is to confirm the process design and demonstrate that the commercial manufacturing process performs as expected

• “By setting criteria, including statistical criteria, that if met lead to the conclusion that the process consistently produces quality product” Grace McNally

• Must be completed before commercial distribution starts


Stage 2: Approach to Performance Qualification

• Is done according to a written protocol

• Is based upon previous knowledge and process understanding

• Considers the effects of scale

• Should use objective measures, e.g. statistical metrics to achieve adequate assurance

• Will require:

• Higher sampling levels

• Additional testing

• Greater scrutiny of process performance

• Full documentation of all test results, monitoring reports


Stage 2: Process Qualification Protocol

• Should include:

• Manufacturing conditions:

Component inputs

• Raw materials, In‐process Intermediates, excipientsOperating parameters for all equipment

Processing limits

• Personnel responsibilities

• Collection and analysis (evaluation) of process data

• Sampling plan

• In‐process, release and characterization tests

• And acceptance criteria for each step


Stage 2: Process Qualification Protocol• Criteria to be applied to process performance

• Statistical methods for analyzing collected data for:

Intra‐batch and inter‐batch variability

Level of process control achieved

• Provisions for the investigation and evaluation of

Deviations from expected conditions

Non‐conforming data (OOS)

• Data should not be excluded without documented, science‐based justification


Stage 2: Process Qualification Protocol • Other Operating Factors

• Documentation of facility/equipment DQ, IQ, OQ

• Specification for personnel training and qualification

• Verification of material sources (components, container/closures, etc.)

• Validation status of analytical methods

• Documentation of review/approval by

• Process Development

• Manufacturing and QC

• Quality Assurance/Validation team

• Senior Management


Stage 2: Process Qualification Protocol Execution

• Must await approval by all relevant departments and QA

• Protocol should be followed exactly

• Complying with cGMP requirements

• Using commercial process and routine procedures (SOPs)

• Starting materials and all reagents from usual sources

• PQ lots manufactured under normal conditions,

• Including environmental control systems, WFI and other services

• By the actual production personnel

• Deviations and excursions should be documented and justified

• Corrective actions must be documented


Stage 2: Process Qualification Report

• Should document and assess the adherence to the protocol

• Summarize and analyze all data collected

• Evaluate unexpected observations and additional data not specified in the protocol

• Summarize and discuss

• Deviations from protocol or SOPs

• Aberrant test results

• Other information that may affect the validity of the process

• Describe all corrective action or changes that should be made toexisting procedures/processes


Stage 2: Process Qualification Report- Conclusions

• State clearly whether:

• The process met the conditions established in the Protocol

• The process is considered to be in a state of control

• The conclusion must be based upon documented justification

• And – the release of the PQ lots by Quality Unit for market distribution

• IF NOT‐ then what should be done, before these conclusions can be reached?

• Report reviewed and approved by appropriate departments and the Quality Unit


Stage 3: Continued Process Verification

• Objective: To ensure the process remains in a state of control

• Complies strictly with the master batch record, operates under cGMP

• Will require a written plan

• At the early stages, higher level of monitoring, sampling, and testing will continue until significant process variability estimates can be made

• Requires examination of many sources of data

• A system to detect unplanned “departures” should be in place

• Evaluation of the data may reveal “process drift”

• Change may be needed to prevent the process from drifting out of control


Stage 3: Verification Monitoring Requirements

• Trends in process parameters and yields

• Ensure that critical process parameters (CPPs) are monitored

• Quality of incoming and in‐process materials

• Measured against specifications for CQAs

• Quality of final product

• Compliance with release specifications

• State of personnel training, including cGMP

• Changes in:

• Facility/equipment

• SOPs


Stage 3: Verification Management

• Data collection and analysis plan should be based upon sound statistical principles

• Describe how trending and calculations are to be performed

• Variation indicators:• Batch records

• Process deviation reports

• OOS findings

• Operators’ comments and errors

• Defect complaints, adverse effect reports

• Investigate problems in variability (OOS) for root cause and implement corrective action


Stage 3: Verification Data Trending

• Evaluate periodically to determine the need for changes in specifications or manufacturing and control procedures

At least annually‐ 21 CFR 211.180(e)

• Analyze data gathered from process monitoring, including operator errors

• Use quantitative and statistical measures where appropriate and feasible

• Study OOS and OOT (out of specification/trend) data

• Assess impact of process and product changes over time

• Feedback into design or qualification stage (as necessary) for significant process shifts or changes


Stage 3: Verification- FDA Recommendations

• Continue monitoring/sampling until sufficient data are availableto generate variability estimates

• Then sampling/monitoring can be reduced to a statistically appropriate level

• Process performance should be re‐assessed periodically

• State conclusions on process capability and stability

• QA to review these conclusions with Production and make recommendations for process improvement, if necessary

• Using a formal system of change control


PAT and Analytic Methods• PAT (process analytic technology) is encouraged superior statistical

power obtained by advanced technologies which detect input and output variability, process drift and react in real time to prevent OOS deviations

• Analytic methods must be scientifically sound to provide meaningful data

• All equipment properly maintained and calibrated

• For Stage 1:• Methods do not need to be validated

• BUT, should be qualified, i.e.:

Specific, sensitive, accurate

Suitable for the task

Reliable Must be scientifically sound, to provide

meaningful data


PAT and Analytic Methods

• For Phase II clinical manufacture

• cGMP‐compliant

• Qualified release tests

• Good stability studies

• For Phase III clinical and commercial manufacture

• Fully validated, cGMP‐compliant release tests

• Stability‐indicating tests


Documentation

• Documentation important at each stage of the validation lifecycle for knowledge capture, communication, transparency across time and amongst disciplines

• It is essential that all process studies and basis for process decisions be documented, including process variables studied andrationale for variables identified as significant

• Output of Stage 1, Process Design

• Initial Master Record of Batch Production and Control (MBR)

• Standard Operating Procedures for Stage 2


Documentation

• Output of Stage 1, Process Design (continued)

• Process flow diagrams/descriptions detailing

Each unit operation

Position in the overall process

Monitoring and control points

All process inputs: starting materials, components, reagents

Expected process outputs


Documentation

• Stages 2 and 3: Process Qualification & Continued Verification

• Records must be cGMP – compliant

• Full SOPs

• Final MBR

• QA review and approval of documentation

• Viral and impurity clearance studies

• Must have full QA oversight ‐ even on small‐scale studies in Design stage

• Keep flow diagrams for all scales and stages for comparability


Summary of Changes in the Guidance• Process Validation is a life‐cycle activity

• No reliance on 3 conformance lots – this is no longer an acceptable criteria and it does not finish there!

• Quality by Design (QbD) is the engine

• Use design of experiments (DOE) to obtain maximum information

• Use Risk Analysis to identify CQAs and CPPs

• Use of multivariate analysis for interaction of CPPs

• No more “worst case” validation runs – true performance qualification

• Intensified monitoring and testing during early commercial production

• Quality system in place for trend analyses and process correction


What Does it Mean for You?


Guidances need to be taken seriously…!• OSAKA, Japan, March 6 /PRNewswire/ ‐‐ Takeda Pharmaceutical Company

Limited today announced that Takeda Global Research and Development Center, Inc., a wholly owned United States (U.S.) subsidiary, was informed as part of regular discussions about the alogliptin New Drug Application (NDA) with the United States Food and Drug Administration (FDA), that although the alogliptinNDA was filed prior to issuance of FDA's December 2008 guidance on new Type 2 diabetes treatments, the FDA will apply these guidelines when reviewing the alogliptin NDA.

• Additionally, the FDA does not believe that the amount of existing alogliptinclinical data is sufficient to meet certain statistical requirements in the new guidance. In December, 2008 the FDA issued "Guidance for Industry: Diabetes Mellitus ‐‐ Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes".

• In October 2008, Takeda received notification from the FDA that it was unable to complete its review of the alogliptin NDA by the original PDUFA date ‐‐October 27, 2008 ‐‐ due to internal resource constraints. The FDA did not raise any issues with the data in the alogliptin NDA at that time. In December 2007, Takeda submitted its NDA for alogliptin to the FDA.

Excerpts from March 6, 2009 press release (emphasis mine)


Current Industry State• Many elements and practices for biologics development are already

in place for a QbD lifecycle approach• Risk management and Design Space largest gaps

• “Big” company ( multiple products)• Some have implemented a QbD quality system and using for

product development; many are at some stage of implementation

• “Medium” company (1 or 2 relatively newer products)• Many planning for or considering QbD quality system and or using

elements of QbD in product development

• “Small” sized company (pipeline only)• “Do we need to worry about QbD?” (Yes, but don’t fear it)

• CMOs• “Studying it”‐ waiting for customers to demand QbD


Desired Industry State

• All companies (small to large) should initiate a program to start implementing QbD and lifecycle process validation if they haven’t done so already

• Once finalized, it will become the “c” in cGMP in the next decade and the de facto standard as “three batch validation” used to be

• Not following the recommendations will increase program and regulatory risk in the future


Some Crucible Points

• Expect all major elements of current draft guidance to be incorporated into final guidance‐ only minor tweaking

• Small companies whose business strategy is to partner can add program value by having a QbD handover package to port into partner’s QbD system

• KISS‐ “keep it simple”

Knowledge management; risk management system; quality system

• Business goals can and should be incorporated into QbD

• E.g., “Invigormab should have a titer of 3 g/L and downstream yield of 60% to be economically viable”



• Initial Target Product Profile and first‐in‐human (FIH) studies

• FIH studies should get to clinic as quickly as possible in a safe/economical manner

• Critical quality attributes will be relatively more focused on patient safety

E.g., sterility (parenterals), aggregates, adventitious agents, endotoxin and DNA residuals

• Many critical quality attributes for efficacy (and potentially for some other safety considerations) for biologics will not be known this early

• QbD can be used to speed time to clinic


• Biological products are complex as are the process parameters that affect critical quality attributes

• Interactions among the numbers factors to make it very difficultto fully understand the relationships among all process parameters, critical process parameters, critical quality attributes, and clinical performance

• Nevertheless, a well characterized Design Space can still be developed that leads to a robust process

• Guidance allows for continued process understanding and improvement during commercialization

• Use of platform and high through‐put technologies, statistics, screening experiments/DOE, use of risk management tools will increase



• Statistics for small population sizes will drive number of runs needed for process qualification

• Population variance for critical process parameters and criticalquality attributes will need to be well characterized as part ofthe design phase

• You need to establish your own rationale and criteria, based on statistics, to generate scientific evidence that the process is capable of making product that can consistently meets quality acceptance criteria

FDA will not say “how many runs are needed”‐ Don’t ask

• Initial cost of process qualification runs will increase from current doing just “3 consecutive batches”‐ plan ahead



• Statistics for verification stage will be driven by establishing new population variance estimates for commercial process

• Good starting point: ASTM E 122 Standard Practice for Calculating Sample Size to Estimate, With Specified Precision, the Average for a Characteristic of a Lot or Process

• BLAs/NDAs

• Guidance says nothing about what should be in a filing

• Transition period may see a blend of QbD and traditional approaches; e.g. Design Space for drug product fill finish only

• Submissions after mid‐decade likely to become increasingly QbD based

• Burden for monitoring and trending data and bringing additional monitoring into the quality system will increase for commercial processes



Concluding Thoughts


• Proactively embrace and manage changes so that they don’t end up managing you • Get started on moving your organization towards life‐cycle

process validation

• Implementation of a QbD life‐cycle approach to validation should be proportionate to and consider your company’s business model and current quality system’s needs

• Companies should always work with the appropriate regulatory authority and industry experts (if needed) to develop the most appropriate process design and validation strategy for a particular product• This point is especially important while the industry and the

regulatory authorities are in transition from the traditional tothe life‐cycle approach

Concluding Thoughts


Thanks

Dr. Alex Kanarek‐ BioProcess Technology Consultants, Inc.


Contact Information

James Blackwell, Ph.D., M.B.A.Senior Consultant

Bioprocess Technology Consultants, Inc.289 Great Road, Suite 303

Acton, MA 01720email: [email protected]

ph: 978-266-9112


Appendix- Other Definitions• Critical Process Parameter‐ “a process input that, when varied beyond a limited

range, has a direct and significant influence on a Critical Quality Attribute (CQA)”Glodek, M., et al. (2006, November/December). Process robustness‐ a PQRI white paper. [Electronic version]. Pharmaceutical Engineering, 6, 1‐11.

• Critical Quality Attribute‐ “…those molecular and biological characteristics found to be useful in ensuring the safety and efficacy of the product…” (ICH Q6B)

• Design Space‐ “the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality” (ICH Q8) Quality System‐ “a management system to direct and control a pharmaceutical company with regard to quality” (ICH Q10)

• QbD‐ “…those molecular and biological characteristics found to be useful in ensuring the safety and efficacy of the product…” (ICH Q6B)

• Quality Risk Management‐ “a systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle” (ICH Q9)

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